Understanding tumor metabolism holds the promise of new insights into cancer biology, diagnosis and treatment.Targeting tumor metabolism has re-emerged over the last decade as a potential source of new cancer therapies. There are several means by which human gliomas metabolism has been assessed: through the metabolome of plasma collected from the cubital vein, through metabolomics analysis of blood collected from resected cancer tissue or cerebral spinal fluid, through imaging with NMR and through assessment of isotope enrichment in glioma tissue after intra-operative infusion with 13C-labeled nutrients. To date, however, direct measurement of metabolites consumption and production by gliomas in patients is technically difficult.

We develop a method, named CARVE, paired analysis of Cancer ARterial-VEnous metabolome, that is based on the prediction that gliomas consume metabolites from the arterial blood in appreciable quantities, and that these metabolites are present at significantly lower concentrations in venous blood downstream of the glioma. Conversely, metabolites produced and secreted by gliomas accumulate in venous blood downstream of the glioma relative to the arterial supply. Through the comparison of plasma metabolomes between the arterial supply and venous drainage, we exclude the interpatient variation and characterized multiple metabolites that are consumed and produced by gliomas in vivo from patients.This strategy greatly increases the chance of identifying metabolites consumed or produced by gliomas, which are impossible to detect in blood samples from the dorsal pedal vein or cubital vein, where blood samples have traditionally been collected for metabolomic analysis.It has encouraged us to use a similar strategy to perform metabolomic analysis of other cancers in patients or animal models. More follow-up experiments need to be performed in the future.

Current treatment methods for patients with gliomas are hampered by a poor understanding of underlying biology. Glial cells are critical for brain metabolism, neuronal protection, and cell-cell communication. As a group with long-term experience in studying the function and development of astrocytes and NG2 glia, we are interested in how gliomas interact with adjacent normal glial cells and how glial cells create a microenvironment that influences glioma cell survival, proliferation, and invasion.

             NG2 glial cell                            An immature astrocyte                Astrocyte & its endfeet

Glia-Glioma Interactions

The brain consists of multiple cell types that form a complex neuron-glia-blood vasculature network. During glioma (brain tumor) development, tumor cells infiltrate normal brain tissue and interact with adjacent stromal cells in this network . The network provides glioma cells with an appropriate environment for colonization, growth and infiltration. However, the role of normal glial cells, which constitute 50 percent of cells in the human brain and are critical for a number of functions (brain metabolism, neuronal protection and cell-cell communication), in glioma progression is poorly understood. Improving our understanding of glia-glioma interactions and discovering the underlying mechanisms are critical for the diagnosis, prognosis and treatment of pediatric glioma and necessary to identify new therapeutic targets.

In vivo imaging of growth of gliomas in mouse brains

We are currently investigating if and how different types of glial cells, especially astrocytes, create a microenvironment that promotes glioma cell survival, proliferation and invasion. This includes characterization of the fate and potential functional alterations of astrocytes adjacent to gliomas in vivo. We will perform longitudinal time-lapse imaging to characterize astrocyte properties (survival, proliferation and progeny) within and close to gliomas at different developmental stages. This will provide researchers with a functional paradigm for glioma growth from its initiation through the late stage.

Time-lapse imaging of growing gliomas in mouse brain (green, glioma cells; read, astrocytes)